title: Hepatocyte growth factor/c-Met signaling is required for β-cell regeneration.
abstract: Hepatocyte growth factor (HGF) is a mitogen required for β-cell replication during pregnancy. To determine whether HGF/c-Met signaling is required for β-cell regeneration, we characterized mice with pancreatic deletion of the HGF receptor, c-Met (PancMet KO mice), in two models of reduced β-cell mass and regeneration: multiple low-dose streptozotocin (MLDS) and partial pancreatectomy (Ppx). We also analyzed whether HGF administration could accelerate β-cell regeneration in wild-type (WT) mice after Ppx. Mouse islets obtained 7 days post-Ppx displayed significantly increased c-Met, suggesting a potential role for HGF/c-Met in β-cell proliferation in situations of reduced β-cell mass. Indeed, adult PancMet KO mice displayed markedly reduced β-cell replication compared with WT mice 7 days post-Ppx. Similarly, β-cell proliferation was decreased in PancMet KO mice in the MLDS mouse model. The decrease in β-cell proliferation post-Ppx correlated with a striking decrease in D-cyclin levels. Importantly, PancMet KO mice showed significantly diminished β-cell mass, decreased glucose tolerance, and impaired insulin secretion compared with WT mice 28 days post-Ppx. Conversely, HGF administration in WT Ppx mice further accelerated β-cell regeneration. These results indicate that HGF/c-Met signaling is critical for β-cell proliferation in situations of diminished β-cell mass and suggest that activation of this pathway can enhance β-cell regeneration.
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Alvarez-Perez
authors.forename: Sara
authors.initials: S
authors.lastname: Ernst
authors.forename: Cem
authors.initials: C
authors.lastname: Demirci
authors.forename: Gabriella P
authors.initials: GP
authors.lastname: Casinelli
authors.forename: Jose Manuel D
authors.initials: JM
authors.lastname: Mellado-Gil
authors.forename: Francisco
authors.initials: F
authors.lastname: Rausell-Palamos
authors.forename: Rupangi C
authors.initials: RC
authors.lastname: Vasavada
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocaña
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010180:Pancreatectomy; D011247:Pregnancy; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met